The influence of MIR137 on white matter fractional anisotropy and cortical surface area in individuals with familial risk for psychosis.

The rs1625579 variant near the microRNA-137 (MIR137) gene is one of the best-supported schizophrenia variants in genome-wide association studies (GWAS), and microRNA-137 functionally regulates other GWAS identified schizophrenia risk variants. Schizophrenia patients with the MIR137 rs1625579 risk genotype (homozygous for the schizophrenia risk variant) also have aberrant brain structure. It is unclear if the effect of MIR137 among schizophrenia patients is due to potential epistasis with genetic risk for schizophrenia or other factors of the disorder. Here, we investigated the effect of MIR137 genotype on white matter fractional anisotropy (FA), cortical thickness (CT), and surface area (SA) in a sample comprising healthy control subjects, and individuals with familial risk for psychosis (first-degree relatives of patients with schizophrenia or bipolar disorder; N=426). In voxel-wise analyses of FA, we observed a significant genotype-by-group interaction (PFWE<0.05). The familial risk group with risk genotype had lower FA (PFWE<0.05), but there was no genetic association in controls. In vertex-wise analyses of SA, we also observed a significant genotype-by-group interaction (PFWE<0.05). Relatives with MIR137 risk genotype had lower SA, however the risk genotype was associated with higher SA in the controls (all PFWE<0.05). These results show that MIR137 risk genotype is associated with lower FA in psychosis relatives that is similar to previous imaging-genetics findings in patients with schizophrenia. Furthermore, MIR137 genotype may also be a risk factor in a subclinical population with wide reductions in white matter FA and cortical SA.

Differential responses of the dorsomedial prefrontal cortex and right posterior superior temporal sulcus to spontaneous mentalizing.

Previous research suggests a role of the dorsomedial prefrontal cortex (dmPFC) in metacognitive representation of social information, while the right posterior superior temporal sulcus (pSTS) has been linked to social perception. This study targeted these functional roles in the context of spontaneous mentalizing. An animated shapes task was presented to 46 subjects during functional magnetic resonance imaging. Stimuli consisted of video clips depicting animated shapes whose movement patterns prompt spontaneous mentalizing or simple intention attribution. Based on their differential response during spontaneous mentalizing, both regions were characterized with respect to their task-dependent connectivity profiles and their associations with autistic traits. Functional network analyses revealed highly localized coupling of the right pSTS with visual areas in the lateral occipital cortex, while the dmPFC showed extensive coupling with instances of large-scale control networks and temporal areas including the right pSTS. Autistic traits were related to mentalizing-specific activation of the dmPFC and to the strength of connectivity between the dmPFC and posterior temporal regions. These results are in good agreement with the hypothesized roles of the dmPFC and right pSTS for metacognitive representation and perception-based processing of social information, respectively, and further inform their implication in social behavior linked to autism. Hum Brain Mapp 38:3791-3803, 2017. © 2017 Wiley Periodicals, Inc.

Influence of Familial Risk for Depression on Cortico-Limbic Connectivity During Implicit Emotional Processing.

Imbalances in cortico-limbic activity and functional connectivity (FC) supposedly underlie biased emotional processing and present putative intermediate phenotypes (IPs) for major depressive disorder (MDD). To prove the validity of these IPs, we assessed them in familial risk. In 70 healthy first-degree relatives of MDD patients and 70 controls, brain activity and seed-based amygdala FC were assessed during an implicit emotional processing task for fMRI containing angry and fearful faces. Using the generalized psychophysiological interaction approach, amygdala FC was assessed (a) across conditions to provide comparable data to previous studies and (b) compared between conditions to elucidate its implications for emotional processing. Associations of amygdala FC with self-reported negative affect were explored post hoc. Groups did not differ in brain activation. In relatives, amygdala FC across conditions was decreased with superior and medial frontal gyrus (SFG, MFG) and increased with subgenual and perigenual anterior cingulate cortex (sgACC, pgACC). NA was inversely correlated with amygdala FC with MFG, pgACC and their interaction in relatives. Relatives showed aberrant condition-dependent modulations of amygdala FC with visual cortex, thalamus and orbitofrontal cortex. Our results do not support imbalanced cortico-limbic activity as IP for MDD. Diminished amygdala-dorsomedial prefrontal FC in relatives might indicate insufficient regulatory capacity, which appears to be compensated by ventromedial prefrontal regions. Differential task-dependent modulations of amygdala FC are discussed as a stronger involvement of automatic instead of voluntary emotional processing pathways. Reliability and etiological implications of these results should be investigated in future studies including longitudinal designs and patient-risk-control comparisons.

Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function.

Schizophrenia is increasingly recognized as a disorder of distributed neural dynamics, but the molecular and genetic contributions are poorly understood. Recent work highlights a role for altered N-methyl-d-aspartate (NMDA) receptor signaling and related impairments in the excitation-inhibitory balance and synchrony of large-scale neural networks. Here, we combined a pharmacological intervention with novel techniques from dynamic network neuroscience applied to functional magnetic resonance imaging (fMRI) to identify alterations in the dynamic reconfiguration of brain networks related to schizophrenia genetic risk and NMDA receptor hypofunction. We quantified "network flexibility," a measure of the dynamic reconfiguration of the community structure of time-variant brain networks during working memory performance. Comparing 28 patients with schizophrenia, 37 unaffected first-degree relatives, and 139 healthy controls, we detected significant differences in network flexibility [F(2,196) = 6.541, P = 0.002] in a pattern consistent with the assumed genetic risk load of the groups (highest for patients, intermediate for relatives, and lowest for controls). In an observer-blinded, placebo-controlled, randomized, cross-over pharmacological challenge study in 37 healthy controls, we further detected a significant increase in network flexibility as a result of NMDA receptor antagonism with 120 mg dextromethorphan [F(1,34) = 5.291, P = 0.028]. Our results identify a potential dynamic network intermediate phenotype related to the genetic liability for schizophrenia that manifests as altered reconfiguration of brain networks during working memory. The phenotype appears to be influenced by NMDA receptor antagonism, consistent with a critical role for glutamate in the temporal coordination of neural networks and the pathophysiology of schizophrenia.

Specificity, reliability and sensitivity of social brain responses during spontaneous mentalizing.

The debilitating effects of social dysfunction in many psychiatric disorders prompt the need for systems-level biomarkers of social abilities that can be applied in clinical populations and longitudinal studies. A promising neuroimaging approach is the animated shapes paradigm based on so-called Frith-Happé animations (FHAs) which trigger spontaneous mentalizing with minimal cognitive demands. Here, we presented FHAs during functional magnetic resonance imaging to 46 subjects and examined the specificity and sensitivity of the elicited social brain responses. Test-retest reliability was additionally assessed in 28 subjects within a two-week interval. Specific responses to spontaneous mentalizing were observed in key areas of the social brain with high sensitivity and independently from the variant low-level kinematics of the FHAs. Mentalizing-specific responses were well replicable on the group level, suggesting good-to-excellent cross-sectional reliability [intraclass correlation coefficients (ICCs): 0.40-0.99; dice overlap at Puncorr<0.001: 0.26-1.0]. Longitudinal reliability on the single-subject level was more heterogeneous (ICCs of 0.40-0.79; dice overlap at Puncorr<0.001: 0.05-0.43). Posterior temporal sulcus activation was most reliable, including a robust differentiation between subjects across sessions (72% of voxels with ICC>0.40). These findings encourage the use of FHAs in neuroimaging research across developmental stages and psychiatric conditions, including the identification of biomarkers and pharmacological interventions.

Altered Functional Subnetwork During Emotional Face Processing: A Potential Intermediate Phenotype for Schizophrenia.

IMPORTANCE: Although deficits in emotional processing are prominent in schizophrenia, it has been difficult to identify neural mechanisms related to the genetic risk for this highly heritable illness. Prior studies have not found consistent regional activation or connectivity alterations in first-degree relatives compared with healthy controls, suggesting that a more comprehensive search for connectomic biomarkers is warranted. OBJECTIVES: To identify a potential systems-level intermediate phenotype linked to emotion processing in schizophrenia and to examine the psychological association, task specificity, test-retest reliability, and clinical validity of the identified phenotype. DESIGN, SETTING, AND PARTICIPATIONS: The study was performed in university research hospitals from June 1, 2008, through December 31, 2013. We examined 58 unaffected first-degree relatives of patients with schizophrenia and 94 healthy controls with an emotional face-matching functional magnetic resonance imaging paradigm. Test-retest reliability was analyzed with an independent sample of 26 healthy participants. A clinical association study was performed in 31 patients with schizophrenia and 45 healthy controls. Data analysis was performed from January 1 to September 30, 2014. MAIN OUTCOMES AND MEASURES: Conventional amygdala activity and seeded connectivity measures, graph-based global and local network connectivity measures, Spearman rank correlation, intraclass correlation, and gray matter volumes. RESULTS: Among the 152 volunteers included in the relative-control sample, 58 were unaffected first-degree relatives of patients with schizophrenia (mean [SD] age, 33.29 [12.56]; 38 were women), and 94 were healthy controls without a first-degree relative with mental illness (mean [SD] age, 32.69 [10.09] years; 55 were women). A graph-theoretical connectivity approach identified significantly decreased connectivity in a subnetwork that primarily included the limbic cortex, visual cortex, and subcortex during emotional face processing (cluster-level P corrected for familywise error = .006) in relatives compared with controls. The connectivity of the same subnetwork was significantly decreased in patients with schizophrenia (F = 6.29, P = .01). Furthermore, we found that this subnetwork connectivity measure was negatively correlated with trait anxiety scores (P = .04), test-retest reliable (intraclass correlation coefficient = 0.57), specific to emotional face processing (F = 17.97, P < .001), and independent of gray matter volumes of the identified brain areas (F = 1.84, P = .18). Replicating previous results, no significant group differences were found in face-related amygdala activation and amygdala-anterior cingulate cortex connectivity (P corrected for familywise error =.37 and .11, respectively). CONCLUSIONS AND RELEVANCE: Our results indicate that altered connectivity in a visual-limbic subnetwork during emotional face processing may be a functional connectomic intermediate phenotype for schizophrenia. The phenotype is reliable, task specific, related to trait anxiety, and associated with manifest illness. These data encourage the further investigation of this phenotype in clinical and pharmacologic studies.

Traces of human migrations in Helicobacter pylori populations.

Helicobacter pylori, a chronic gastric pathogen of human beings, can be divided into seven populations and subpopulations with distinct geographical distributions. These modern populations derive their gene pools from ancestral populations that arose in Africa, Central Asia, and East Asia. Subsequent spread can be attributed to human migratory fluxes such as the prehistoric colonization of Polynesia and the Americas, the neolithic introduction of farming to Europe, the Bantu expansion within Africa, and the slave trade.